Our fundamental hypothesis is that readily identifiable biomarkers, including p53, thymidylate synthase and enzymes in the glutathione pathway are critical determinants of response and long term outcome for patients receiving chemotherapy and/or radiation for head and neck cancer. These biomarkers may be developed both as prognostic indicators to guide therapy and as targets for strategies which will enhance the efficacy of cisplatin based chemotherapy in this set of diseases. We present preliminary data which strongly suggest that overexpression of p53, thymidylate synthase and glutathione s-transferase (pi) are associated with poor outcome in patients receiving chemotherapy for head and neck cancer. We believe they can be developed as clinically important markers for patients with head and neck cancer. On the basis of our preliminary data, we propose the following aims: 1. To confirm the prognostic significance of p53, glutathione s-transferase and thymidylate synthase in patients participating in clinical trials for head and neck cancer. 2. To confirm the prognostic significance of p53, glutathione s-transferase and thymidylate synthase in a control group of patients receiving standard surgery and/or radiation therapy. 3. To develop tissue microarrays based on the samples in specific aims 1 and 2 for focused screening and validation of additional cellular factors as determinants of clinical response and outcome.